Chen Yuanyuan, Zhang Zongying, Yao Yuan, Zhou Xiaorong, Ling Yong, Mao Liming, Gu Zhifeng
Graduate School, Dalian Medical University, Dalian 116044, China.
Department of Rheumatology, Affiliated Hospital of Nantong University, Nantong 226019, China.
Curr Issues Mol Biol. 2025 Jan 9;47(1):38. doi: 10.3390/cimb47010038.
Rheumatoid arthritis (RA) is an autoimmune disorder that leads to severe cartilage deterioration and synovial impairment in the joints. Previous studies have indicated that the aberrant activation of the NLRP3 inflammasome in synovial macrophages plays a significant role in the pathogenesis of RA and has been regarded as a therapeutic target for the disease. In this study, we synthesized a novel canthin-6-one alkaloid, namely methyl canthin-6-one-2-carboxylate (Cant), and assessed its effects on NLRP3 inflammasome activation in macrophages. Our data reveal that exposure to Cant significantly suppressed the transcription and secretion of multiple pro-inflammatory mediators, including IL-1β, IL-6, IL-18, TNF-α, NO, and COX2, in a dose-dependent manner. These alterations were associated with changes in the activation of various signaling pathways, including NF-kB, MAPK, and PI3K-AKT pathways. Notably, pretreatment with Cant significantly reduced LPS/ATP-induced activation of the NLRP3 inflammasome, as evidenced by the decline in the cleaved forms of IL-1β and caspase-1 in cell culture supernatants of BMDMs. Regarding the mechanisms, our data show that Cant could enhance the expression of Nrf2 in macrophages, which play an inhibitory role in ROS production. Collectively, our data demonstrate that Cant might suppress the activation of the NLRP3 inflammasome by upregulating the production of Nrf2, suggesting that Cant could serve as a candidate for the further development of anti-RA drugs.
类风湿性关节炎（RA）是一种自身免疫性疾病，会导致关节软骨严重退化和滑膜损伤。先前的研究表明，滑膜巨噬细胞中NLRP3炎性小体的异常激活在RA的发病机制中起重要作用，并被视为该疾病的治疗靶点。在本研究中，我们合成了一种新型的咔啉-6-酮生物碱，即6-羧甲基咔啉-6-酮（Cant），并评估了其对巨噬细胞中NLRP3炎性小体激活的影响。我们的数据显示，暴露于Cant以剂量依赖的方式显著抑制了多种促炎介质的转录和分泌，包括IL-1β、IL-6、IL-18、TNF-α、NO和COX2。这些改变与包括NF-κB、MAPK和PI3K-AKT途径在内的各种信号通路激活的变化有关。值得注意的是，用Cant预处理显著降低了LPS/ATP诱导的NLRP3炎性小体的激活，这在BMDM细胞培养上清液中IL-1β和caspase-1的裂解形式的下降中得到了证实。关于其机制，我们的数据表明，Cant可以增强巨噬细胞中Nrf2的表达，Nrf2对ROS的产生起抑制作用。总体而言，我们的数据表明，Cant可能通过上调Nrf2的产生来抑制NLRP3炎性小体的激活，这表明Cant可作为抗RA药物进一步开发的候选药物。
